1. Field of the Invention
The present invention relates to a method and apparatus for dispensing chemical reagents and other liquids onto a substrate such as to form a diagnostic test strip or clinical test array and, in particular, to a method and apparatus adapted for high-speed, precision dispensing of high-density "dot" arrays and other patterns onto a receptive membrane, high-density micro-well plate or other suitable receptacle.
2. Description of the Related Art
Clinical testing of various bodily fluids conducted by medical personnel are well-established tools for medical diagnosis and treatment of various diseases and medical conditions. Such tests have become increasingly sophisticated, as medical advancements have led to many new ways of diagnosing and treating diseases.
The routine use of clinical testing for early screening and diagnosis of diseases or medical conditions has given rise to a heightened interest in simplified procedures for such clinical testing that do not require a high degree of skill or which persons may conduct on themselves for the purpose of acquiring information on a physiologically relevant condition. Such tests may be carried out with or without consultation with a health care professional. Contemporary procedures of this type include blood glucose tests, ovulation tests, blood cholesterol tests and tests for the presence of human chorionic gonadotropin in urine, the basis of modern home pregnancy tests. Other tests or clinical procedures have been developed for genetic screening or genetic testing, such as for research or medical diagnostics. For example, such research or screening may be conducted via parallel testing of many individual droplets of a fluid sample on a high-density micro-well plate.
One of the most frequently used devices in clinical chemistry is the test strip or dip stick. These devices are characterized by their low cost and simplicity of use. Essentially, the test strip is placed in contact with a sample of the body fluid to be tested. Various reagents incorporated on the test strip react with one or more analytes present in the sample to provide a detectable signal.
Most test strips are chromogenic whereby a predetermined soluble constituent of the sample interacts with a particular reagent either to form a uniquely colored compound, as a qualitative indication of the presence or absence of the constituent, or to form a colored compound of variable color intensity, as a quantitative indication of the amount of the constituent present. These signals may be measured or detected either visually or via a specially calibrated machine.
For example, test strips for determining the presence or concentration of leukocyte cells, esterase or protease in a urine sample utilize chromogenetic esters which produce an alcohol product as a result of hydrolysis by esterase or protease. The intact chromogenetic ester has a color different from the alcohol hydrolysis product. The color change generated by hydrolysis of the chromogenetic ester, therefore provides a method of detecting the presence or concentration of esterase or protease, which in turn, is correlated to the presence or concentration of leukocyte cells. The degree and intensity of the color transition is proportional to the amount of leukocyte esterase or HLE detected in the urine. See, for example, U.S. Pat. No. 5,464,739.
The emergence and acceptance of such diagnostic test strips and other clinical screening methods as a component of clinical testing and health care in general has led to the development of a number of quality diagnostic test strip and clinical screening products. Moreover, the range and availability of such products is likely to increase substantially in the future.
Because test strips are used to provide both quantitative and qualitative measurements, it is extremely important to provide precision and uniformity in the placement and distribution of the reagents on the test strip substrate. The chemistry is often quite sensitive and good medical practice requires that the testing system be extremely accurate and precise as possible. When automated systems are used, it is particularly important to ensure that the test strips are reliable and that the measurements taken are quantitatively accurate.
In some cases it is necessary or desirable to provide precise patterns or dot arrays (either contiguous or non-contiguous) of reagent on a test strip, comprising different reagents and/or reagent concentrations. For example, some test strips provide multiple test areas that are serially arranged in an array so that multiple tests may be performed using a single test strip. U.S. Pat. No. 5,183,742, for instance, discloses a test strip having multiple side-by-side detection regions or zones for simultaneously performing various tests upon a single sample of body fluid. Such test strips may be used, for example, to determine levels of glucose, protein, and the pH of a single blood sample.
When such patterns (particularly overlapping and/or complex patterns) are used, it is critical that the patterns be precisely and repeatably placed on each substrate such that they may be precisely registered with a sample to be tested and/or other reagent patterns placed on the same or another mating substrate or mask. Precise registration is also required when using automated pick-and-place ("suck-and-spit") fluid handling systems. But repeatably dispensing reagents or other fluids onto a substrate in this precise manner is a highly difficult task to accomplish. The viscosities and other flow properties of the reagents, their reactiveness with the substrate or other reagents vary from reagent to reagent, and even from lot to lot of the same reagent. It is often difficult to control the dispensing apparatus to form sharp lines or other geometric shapes having uniform concentrations of reagent or other desired characteristics. It is particularly difficult provide precision and accuracy in the placement of reagent patterns on the same or different substrates. Again, this is primarily attributable to the nature of the reagents and the substrate.
Currently available dispensing methods and equipment are limited in their ability to provide the required degree of precision and accuracy, particularly on a high-speed production scale. For example, conventional reagent dispensing equipment may include a solenoid valve dispensing head mounted on or in association with a programmable X, X-Y or X-Y-Z table or carriage. The motion of the table may be electronically coordinated with the operation of the dispenser so that the dispenser can be caused to dispense one or more droplets of reagent or other fluid at any one of a number of locations on the substrate defined by the position of the X and Y axes of the X-Y table. In operation, the X-Y table moves the substrate or the dispensing head to a desired location and then stops while the dispenser is caused to dispense the desired amount of reagent onto the substrate at the desired location. After each dispensing operation is completed, the X-Y table then moves to the next location and the process repeats for as many locations as are necessary to complete the pattern.
This process of stopping and starting the X-Y table after each dispensing operation is time consuming because of the settling time of the system upon completion of each cycle. Each time the table is instructed to stop at a desired location, it takes a certain amount of time for the table or carrier platform to come to rest and for any harmonic energy in the system to be dissipated. This settling time can sometimes be as long as a few hundred milliseconds or more, depending upon the mass of the carrier platform and other system characteristics. While such a delay might not be significant for dispensing patterns of only a few dots or dispense locations, such delay becomes quite significant when complex or high-density reagent patterns are used which may be composed of as many as several thousand or more individual dots or dispense locations. This severely and undesirably limits the production speed and output of such equipment.
Conventional "stop-and-go" dispensing equipment and methods are also undesirable from a precision and accuracy standpoint. While statistical studies may be performed to determine the appropriate settling time to allot before each dispensing operation, there may be variances in the system that cannot be easily predicted or controlled. For example, the X-Y table may have a different coefficient of damping at a certain location or range of locations due to uneven wear or lubrication. In that event, an allotted settling time may be too short in some dispensing locations to allow the system to come to complete rest such that accuracy and precision are compromised. But increasing the allotted settling time only slows down production even further and, even then, does not guarantee that other variances in the system or even statistical variances will not have the same degenerative effect.
Often there may be some amount hysteresis effect or "play" in the X-Y table or carrier platform (such as caused by excessive wear), which can cause the dispensing platform to have even more imprecision when using conventional stop-and-go dispensing methods. This is because the carrier platform, when instructed to stop at a particular X-Y location, may tend to overshoot and come to rest at slightly different locations depending, for example, on what direction or at what speed the platform was traveling before it stopped. This condition can be aggravated by excessive wear and tear caused by such repetitive stop and go dispensing operations. While, some of these deficiencies may be mitigated by appropriate maintenance and control of the X-Y table, it greatly increases the difficulty of the task.
Even beyond these significant problems and limitations, current dispensing equipment and methods are often difficult to use when complex reagent patterns are desired. This is because the X-Y table and the dispensing head typically must be manually programmed and coordinated by the user to follow a predetermined series of steps and/or dispensing operations in order to achieve the desired pattern(s). This is a time consuming and repetitive task.